rs146504767

Variant names:

• chr19-38485691-G-A
• rs146504767
• NM_000540.3:c.5036G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38485691-G-A
• chr19-38485691-G-C
• chr19-38485691-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. BS2_Supporting BS1 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024479/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:15
• Conservation: PhyloP100: 9.90
• Publications: 11 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.5036G>A	p.Arg1679His	missense	Exon 34 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.5036G>A	p.Arg1679His	missense	Exon 34 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.5036G>A	p.Arg1679His	missense	Exon 34 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.5036G>A	p.Arg1679His	missense	Exon 34 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.5036G>A		non_coding_transcript_exon	Exon 34 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00113 AC: 277 AN: 245716 AF XY: 0.00119

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00130 AC: 1896 AN: 1458806 Hom.: 3 Cov.: 33 AF XY: 0.00127 AC XY: 922 AN XY: 725896

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86216

European-Finnish (FIN) AF: 0.00173 AC: 88 AN: 50744

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00154 AC: 1710 AN: 1111772

Other (OTH) AF: 0.00131 AC: 79 AN: 60356

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74482

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Malignant hyperthermia, susceptibility to, 1 (7)
-	3	2	not provided (5)
-	1	1	not specified (2)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.099	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.92
Sift	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.71
MVP		1.0
MPC		0.44
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.29
gMVP		0.67
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146504767; hg19: chr19-38976331; COSMIC: COSV62091282;